TRANSGENIC MICE OVEREXPRESSING A DOMINANT-NEGATIVE MUTANT TYPE-II TRANSFORMING-GROWTH-FACTOR-BETA RECEPTOR SHOW ENHANCED TUMORIGENESIS IN THE MAMMARY-GLAND AND LUNG IN RESPONSE TO THE CARCINOGEN 7,12-DIMETHYLBENZ-[ALPHA]-ANTHRACENE

To test the hypothesis that the transforming grow th factor-beta (TGF- beta) system has tumor suppressor activity in the mammary gland, we ha ve generated transgenic mice overexpressing a dominant-negative mutant form of the type II TGF-beta receptor, under the control of the mouse mammary tumor virus-long terminal repeat, High-level expression of th e transgene was observed in the mammary and salivary glands, with lowe r expression in the lung, spleen, and testis, Older nulliparous transg enic mice (9-17 months) showed a marked increase in the incidence and degree of lobulo-alveolar side-branching in the mammary glands when co mpared to wild-type littermates (24.8% of glands examined histological ly versus 14.4%; P = 0.004), suggesting a role for endogenous TGF-beta s in regulating development or maintenance of mammary alveoli, Sponta neous tumorigenesis was unchanged in the transgenic mice, However, fol lowing initiation with the carcinogen 7,12-dimethylbenz[a]anthracene, the transgenic group showed a significant increase in the incidence an d multiplicity of mammary tumors when compared with wild-type litterma tes (40% incidence in transgenic mice versus 22% for wild-type, with 4 of 25 transgenics developing multiple mammary tumors versus 0 of 27 w ild-type; P = 0.03), An early increase in the incidence of lung tumors was also observed in transgenic mice, but no difference between genot ype groups was seen in the incidence of tumors in tissues in which the transgene is not expressed, The data show that the endogenous TGF-bet a system has tumor suppressor activity in the mammary gland and lung.